Primary congenital deficiencies of fibrinolytic inhibitors (alpha-2-antiplasmin [A2AP] and plasminogen activator inhibitor-1 [PAI-1]) are rare, but well-documented causes of bleeding. Hyperfibrinolytic hemorrhage occurs much more commonly as a manifestation of an underlying, systemic process that leads to acquired reduction in circulating levels of a fibrinolytic inhibitor, usually A2AP. Therefore, in evaluating the otherwise healthy patient with thrombosis or hemorrhage, it is advisable to rule out more common etiologies before launching an investigation of the fibrinolytic system.

What features of the presentation will guide me toward possible causes and next treatment steps?

Deep venous thrombosis

Global fibrinolytic deficiency (GFD), as defined by a tissue factor-initiated, tPA-induced clot lysis time (CLT) that is prolonged above the 90th percentile, appears to confer a two-fold increased risk of deep vein thrombosis (DVT). Whereas GFD has been associated with elevated levels of thrombin-activatable fibrinolysis inhibitor (TAFI), there is little evidence for a role for abnormalities in plasminogen, tPA, A2AP, or PAI-1. In addition, patients undergoing partial liver resection display a hypercoagulable state that is due to a reduction in synthesis of both plasminogen and natural anti-coagulants between post-operative days 3 and 7.

The association between GFD and venous thrombosis is substantially increased in the presence of additional prothrombotic risk factors, such as the use of oral contraceptives, the presence of factor V Leiden, or abnormalities in natural anticoagulants such as protein C, protein S, and antithrombin III. Gene mutations in tPA and uPA have not been well-documented in humans and are not associated with thrombosis.

Ligneous mucositis, rather than thrombosis, is the hallmark of congenital plasminogen deficiency

This disorder usually presents in infancy (mean age 9.5 months) with pseudomembrane formation most commonly involving the conjunctiva. However, especially later in life, ligneous mucositis can involve any mucous membrane, including the gingiva, upper and lower respiratory tract, middle ear, gastrointestinal tract, female genital tract, and kidneys. These findings suggest that, while plasmin may be uniquely important for clearing fibrin associated with mucous membranes, other proteases may replace its function within the vasculature.

Bleeding

Fibrinolytic inhibitor deficiencies are rare inherited causes of bleeding. Individuals with congenital PAI-1 deficiency exhibit mild to moderate bleeding, including epistaxis, menorrhagia, and delayed bleeding after surgery or trauma. However, these individuals rarely have the spontaneous bleeding episodes characteristic of hemophilia or other procoagulant deficiencies. Congenital A2AP deficiency is a rare autosomal recessive disorder that presents most often in infancy or childhood with unprovoked and/or delayed bleeding.

Acquired hyperfibrinolysis is a more common cause of bleeding, and is usually associated with an underlying systemic process that leads to depletion of circulating levels of inhibitors, usually A2AP, due to reduced synthesis, urinary loss, tissue deposition, or consumption.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

For the patient with thrombosis or bleeding, initial screening tests should include complete blood (CBC) with differential, platelet count, platelet function analysis, prothrombin time, partial thromboplastin time, and fibrinogen level. In fibrinolytic disorders, the results of these tests are typically normal.

To investigate the etiology of thrombosis, additional tests include assays for the more common inherited hypercoagulable states, including factor V Leiden, prothrombin G20210A, protein C, protein S, and antithrombin III deficiency, and increased factor VIII levels. Acquired thrombophilia can be associated with the presence of anti-phospholipid antibodies. These assays are usually normal in isolated fibrinolytic disorders, but it is important to note that deficiencies in natural anticoagulants and fibrinolytic factors may co-exist in a given patient.

In the past, the euglobulin lysis time (ELT) was widely used to assess global fibrinolytic function. This assay, however, has yielded inconclusive results with respect to the potential role of hypofibrinolysis in thrombosis. The ELT tests only a portion of the fibrinolytic system, and excludes the contribution of TAFI and its activation by the coagulation cascade.

Recently, however, a newer clot lysis assay has emerged. The tissue factor-initiated, tPA-induced clot lysis time (CLT), while not yet widely available, has shown to be prolonged in fibrinolytic deficiency states. In the patient with hyperfibrinolytic bleeding, initial screening tests are normal, but the CLT is reduced. The presence of a shortened CLT in the absence of thrombocytopenia and red cell fragments on the peripheral blood smear would suggest primary fibrinolysis rather than disseminated intravascular coagulation. Abnormalities in ELT or CLT can be further investigated by performing assays for specific fibrinolytic factors.

In addition, viscoelastic coagulation assays (e.g., ROTEM® and TEG®) have gained in popularity because of their rapid readouts related to whole blood clotting time and fibrinolytic activity. However, it is important to note that establishing reference ranges for specific patient groups (e.g., cardiothoracic surgery patients, pregnant women, and pediatric patients) is crucial for accurate interpretation of results.

What conditions can underlie fibrinolytic disorders?

Hypofibrinolysis: intra-abdominal thromboses

Intra-abdominal thromboses, especially Budd-Chiari syndrome or splanchnic vein thrombosis, appear to be associated weakly with global hypofibrinolysis. In the antiphospholipid syndrome, auto-antibodies directed against fibrinolytic proteins (tPA) or their receptors (annexin A2) have been associated with major thromboses; such antibodies may either inhibit fibrinolytic function, or induce prothrombotic cellular activation.

Hyperfibrinolysis: loss of fibrinolytic inhibitors

Loss of fibrinolytic inhibitors can occur in a variety of systemic disorders. In chronic liver disease, or in the anhepatic phase of orthotopic liver transplantation, hyperfibrinolytic bleeding may be associated with reduced synthesis of A2AP. However, because numerous procoagulant factors may also be underproduced, the overall hemostatic picture may be complex.

In the nephrotic syndrome, significant urinary loss of A2AP may lead to bleeding. In amyloidosis, tissue deposition of A2AP may exhaust circulating levels and lead to hemorrhage. In the hemorrhagic phase of acute promyelocytic leukemia, consumption of A2AP induced by excessive plasmin generation is well documented and likely contributes to the bleeding diathesis. High-level expression of the annexin A2/p11 fibrinolytic complex, which stimulates tPA-dependent plasmin generation, has been identified on circulating blast cells in this disorder.

Excessive production of fibrinolytic activators

Excessive production of fibrinolytic activators may also lead to fibrinolytic bleeding. In metastatic prostate cancer, hyperfibrinolysis with hemorrhagic sequelae is thought to reflect overproduction of urokinase. In patients undergoing, cardiopulmonary bypass, blood contact with non-endothelial cell surfaces leads to excessive activation of plasmin. Hyperfibrinolysis also contributes to the coagulopathy of heat stroke. Trauma-associated hyperfibrinolysis is common, and appears to be associated with the combined effects of endothelial cell tPA release due to tissue injury and inhibition of PAI-1 in the setting of shock.

When do you need to get more aggressive tests?

In a patient with thrombosis or abnormal bleeding, and no abnormality in the initial screening tests of platelet and coagulation system function, the diagnosis of an acquired or congenital defect in fibrinolysis should be considered.

In the setting of thrombosis, levels of plasminogen, tPA, uPA, and A2AP appear to have little utility. On the other hand, elevated TAFI and PAI-1 levels have been shown to constitute a risk factor for first or recurrent venous thrombosis. In addition, elevated PAI-1 levels have been associated with myocardial infarction in young males, and a recent study indicated that the plasma PAI-1 level is an independent predictor of cardiovascular disease events in middle-aged subjects.

For the bleeding patient, assays for A2AP and PAI-1 should be performed. An assay for plasmin-A2AP (PAP) (plasmin-alpha2-antiplasmin) complexes can be used as an index of plasmin generation in patients with hyperfibrinolytic bleeding who are receiving treatment for their systemic disease.

What imaging studies (if any) will be helpful?

In addition to laboratory tests and physical examination, imaging studies are useful to document either thrombosis or internal bleeding; however, the choice of diagnostic imaging technique will differ for some specific populations, such as those with recurrent deep vein thrombosis, elderly individuals, and pregnant women. Ultrasound and CT (computed tomography) scan with intravenous contrast are commonly used to detect thrombosis in extremities and within internal organs. A non-contrast CT scan is helpful to screen for moderate-to-large volume bleeding, while radionuclide imaging and angiography are more sensitive tests for small volume intermittent bleeding. Brain MRI (magnetic resonance imaging) can diagnose acute intracranial hemorrhage, including hyperacute hematomas, with close to 100% sensitivity and specificity, within 1 to 6 hours of onset of bleeding or symptoms.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

For the patient with thrombosis, anticoagulation with heparin, warfarin, or one of the newer antithrombin or anti-Xa drugs is a priority to prevent clot extension or embolization. Because individual coagulation factors may undergo depletion during the acute phase of thrombosis, definitive work-up should be deferred until the thrombus has resolved, or at least 3-6 months after the acute event. Patients with increased risk of thrombosis due to reduced overall fibrinolytic function may benefit from anticoagulants or antiplatelet agents.

For the bleeding patient without systemic disease, assays for fibrinolytic function and individual factor levels should be obtained as soon as possible. Hyperfibrinolytic bleeding can usually be controlled with either antifibrinolytic agents (epsilon-aminocaproic acid [EACA] or tranexamic acid), or fresh frozen plasma infusion as a source of fibrinolytic inhibitor activity. In the setting of systemic disease, the underlying cause should be addressed, and bleeding can generally be controlled with antifibrinolytics or plasma.

What other therapies are helpful for reducing complications?

N/A

What should you tell the patient and the family about prognosis?

Congenital, inherited disorders, whether characterized by hypo- or hyper-fibrinolytic function, are lifelong conditions that can be successfully managed. Hypofibrinolysis with risk of thrombosis may require modest therapy with anticoagulants or antiplatelet agents. Congenital hyperfibrinolytic bleeding disorders can be managed with either pharmacologic therapy or factor replacement. For acquired hyperfibrinolysis, treatment of the underlying cause is key.

“What if” scenarios.

For patients with thrombosis who are receiving anticoagulants or antiplatelet agents, the patient should be carefully monitored for bleeding complications with clinical examination and laboratory tests, including CBC, platelet count, and coagulation profiles. EACA can be used empirically to treat severe mucosal bleeding when associated with very low platelet counts (less than 20,000), such as in the setting of periodontal disease. Care must be exercised, however, when using antifibrinolytic agents to treat bleeding in complicated clinical situations in which thrombosis may also occur, because inhibiting fibrinolysis can worsen thrombosis.

Both EACA and tranexamic acid are generally well-tolerated, but patients must be observed for possible thrombotic complications. Additionally, thrombotic ureteral obstruction can occur in patients with upper urinary tract bleeding, and such patients should be treated with antifibrinolytics only after careful consideration. The risks of ureteral obstruction can be decreased by insuring high urine flow.

Thrombotic complications can occur in patients with hypercoagulability or disseminated intravascular coagulation (DIC), who also receive antifibrinolytics. Myonecrosis is a rare complication of fibrinolytic therapy. Minor complications include rash and abdominal discomfort; nausea and vomiting have also been reported.

Pathophysiology

Fibrinolysis is the tightly regulated process by which cross-linked fibrin is proteolyzed into a series of defined degradation products.

In this pathway, a series of activators, inhibitors, cofactors, and cell surface receptors govern the overall generation of plasmin from its precursor plasminogen, and also control activity of plasmin itself.

In brief, circulating inactive plasminogen is converted to active plasmin by the action of either of two serine proteases, tPA or uPA. Plasmin and its activators are regulated by serine protease inhibitors, primarily A2AP and PAI-1, respectively. In addition, a plasma carboxypeptidase, TAFIg., can modify the C-terminal lysine residues on partially degraded fibrin, which are binding sites for plasminogen and tPA; their removal by TAFI impairs plasmin generation. Fibrin is a potent cofactor for the activation of plasminogen by tPA, but not uPA. A number of cell surface receptors, such as the annexin A2/p11 complex, may also contribute to fibrinolytic balance by stimulating the catalytic efficiency of plasmin generation on the surface of blood vessels and circulating cells.

What other clinical manifestations may help me to diagnose disorders of fibrinolysis?

Hypofibrinolysis

Congenital occlusive hydrocephalus, requiring surgical treatment, has been observed in several children with plasminogen deficiency and ligneous conjunctivitis. Juvenile colloid milium, a rare skin disorder, is characterized by the appearance of small, translucent, yellow-brown papules in sun-exposed areas in children with plasminogen deficiency.

Livedoid vasculopathy

Livedoid vasculopathy, an occlusive vascular disorder affecting small blood vessels of the lower extremities, has been associated with elevated levels of PAI-1 due to a homozygous promoter polymorphism (4G/4G) that increases its production; it has been successfully treated with tPA infusions. Ulcerations resulting from this disorder lead to the development of white atrophic scars (atrophie blanche), which have also been associated with a marked defect in post-venous occlusion release of tPA.

Hyperfibrinolysis

Intramedullary diaphyseal hemorrhage may be a presenting feature of A2AP deficiency. Delayed umbilical bleeding, as is also seen in factor XIII deficiency, has been reported in neonates with A2AP deficiency.

What other additional laboratory studies may be ordered?

Hypofibrinolysis

Due to the striking homology of its apoprotein with plasminogen, lipoprotein(a) [Lp(a)], when present in elevated concentrations, may block binding of plasminogen to either fibrin or its cell surface receptors, leading to a loss of fibrinolytic activity. Venous thromboembolism (VTE) has been associated with elevated Lp(a), and levels over 30 mg/dl are considered to be an independent risk factor for VTE (1.6-fold).

TAFI

TAFI is a potential risk factor for thrombosis. Elevated levels (greater than 90th percentile) confer a 1.7-fold relative risk of DVT. TAFI is a carboxypeptidase that removes C-terminal lysine residues from fibrin, thereby eliminating sites of plasminogen binding and activation. When bound to an endothelial cell receptor known as thrombomodulin, thrombin activates TAFI, allowing it to modify plasminogen binding sites on fibrin.

Hyperfibrinolysis

Factor V Quebec is a very rare autosomal dominant bleeding disorder. It arises when platelets harbor increased quantities of uPA due to a duplication of the uPA gene. Excess uPA in platelet granules is thought to activate plasmin, which then degrades granule stores of factor V, fibrinogen, and other procoagulant factors. Such patients present with moderately severe bleeding, that is out of proportion to the associated mild thrombocytopenia. Bleeding is typically delayed, occurring 12-24 hours after surgery, dental extraction, or trauma. Definitive diagnosis requires gene sequencing.